Androgens are responsible for many physiological functions in both males and females. Androgen action is mediated by specific intracellular hormone receptors expressed in androgen responsive cells. Testosterone, the major circulating androgen, is secreted by Leydig cells of the testes under the stimulation of pituitary-derived luteinizing hormone (LH). However, reduction of the 4, 5 double bond of testosterone to dihydrotestosterone (DHT) is required in some target tissues, such as prostate and skin, for androgen action. Steroid 5.alpha.-reductases in target tissues catalyze conversion of testosterone to DHT in an NADPH dependent fashion as shown in Scheme A. ##STR1##
The requirement for DHT to act as an agonist in these target tissues has been highlighted by studies of steroid 5.alpha.-reductase deficient individuals who have vestigial prostate glands and do not suffer from acne vulgaris or male pattern baldness (see McGinley, J. et al., The New England J. of Medicine, 300, 1233 (1979)). Thus, inhibition of the conversion of testosterone to DHT in these target tissues is anticipated to be useful in the treatment of a variety of androgen responsive diseases, e.g., benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism.
Additionally, it has recently been discovered that two isozymes of 5.alpha.-reductase exist in humans which differ in their tissue distribution, affinity for testosterone, pH profile and sensitivity to inhibitors (see Russell, D. W. et al., J. Clin. Invest., 89, 293 (1992); Russell, D. W. et al., Nature, 354, 159 (1991)). The steroid 5.alpha.-reductase deficient individuals studied by Imperato-McGinley are deficient in the type 2, 5.alpha.-reductase enzyme (Russell, D. W. et al, J. Clin. Invest, 90, 799 (1992); Russell, D. W. et at., New England J. Med., 327, 1216 (1992)), which is the predominant isozyme present in the prostate, while the type 1 isozyme is predominant in the skin. The relative value of isozyme specific and dual inhibitors of the two isozymes of 5.alpha.-reductase will depend upon the type of disease treated (benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness or hirsutism) as well as the stage of the disease (prevention versus treatment) and the anticipated side-effects in the intended patients (for example treatment of acne vulgaris in pubescent males).
Because of their valuable therapeutic potential, testosterone 5.alpha.-reductase inhibitors [hereinafter "5.alpha.-reductase inhibitors"] have been the subject of active research worldwide. For example, see: Hsia, S. and Voight, W., J. Invest. Derm., 62, 224 (1973); Robaire, B. et al., J. Steroid Biochem., 8, 307 (1977); Petrow, V. et al., Steroids, 38, 121 (1981); Liang, T. et al., J. Steroid Biochem., 19, 385 (1983); Holt, D. et al., J. Med. Chem., 33, 937 (1990); U.S. Pat. No. 4,377,584, U.S. Pat. No. 4,760,071 and U.S. Pat. No. 5,017,568. Two particularly promising 5.alpha.-reductase inhibitors are MK-906 (Merck), known by the generic name, finasteride, and marketed under the trademark, Proscar; and SKF-105657 (SmithKline Beecham), shown in Scheme B. ##STR2##
The potent inhibition of bovine adrenal and porcine granulosa cell 3.beta.-hydroxy-.DELTA..sup.5- steroid dehydrogenase / 3-keto-.DELTA..sup.5 -steroid isomerase (3BHSD) by the 4-azasteroid derivative, 4-MA, shown in Scheme C and not by the drug finasteride ##STR3## (Tan, C. H.; Fong, C. Y.; Chan, W. K. Biochem. Biophys. Res. Comm., 144, 166 (1987) and Brandt, M.; Levy, M. A. Biochemistry, 28, 140 (1989)) along with the critical role of 3BHSD in steroid biosynthesis (Potts, G. O. et al., Steroids, 32, 257 (1978)), suggests that optimal inhibitors of type 1 and 2 5.alpha.-reductase should also be selective versus human adrenal 3BHSD. The importance of selectivity in 5.alpha.-reductase inhibitors has been emphasized by reports of hepatotoxicity in certain 4-azasteroids such as 4-MA (McConnell, J. D. The Prostate Suppl., 3, 49 (1990) and Rasmusson, G. H. et al. J. Med. Chem. 27, 1690 (1984)).